Release-regulating preparations comprising biphenyldiamine derivatives

ABSTRACT

A medicinal composition containing one or more compounds selected from the compounds represented by the following formula (I), salts of these compounds, solvates of these compounds and solvates of these salts and being capable of reducing the contact of the compounds with the components in the bile or pancreatic juice.

TECHNICAL FIELD

The present invention relates to medicinal compositions containing a newcompound.

More particularly, the invention relates to medicinal compositionseffective for improving the absorption of said new compound throughdigestive tracts by reducing the contact of the compound with componentsof bile or pancreatic juice secreted in the duodenum.

BACKGROUND ARTS

Medicinal compositions added with cyclodextrins and lipophilicsubstances such as medium-chain fatty acid triglycerides were disclosedin the specifications of the JP-A 9-2977 (hereinafter, JP-A means“Japanese Unexamined Patent Application”.) and JP-A 10-231254 as thecompositions to improve the absorption of aromatic amidine derivativesthrough the digestive tracts. However, the long-term safety ofcyclodextrins administered by peroral administration is not sufficientlyconfirmed and the lipophilic substance such as medium-chain triglycerideis possible to cause the adverse effects on the digestive tracts such asdiarrhea and the risk of the failure in the barrierness of the digestivetract membrane. Further, the absorption-improving effect shown in theseinventions is not expectable to be selective to the compound and havehigh safety. Specification of WO 98/3202 disclosed a medicinalcomposition containing an anion exchange resin with respect to aromaticamidine derivatives. However, cholestyramine shown as a preferableexample of anion exchange resin in the specification is the activecomponent itself used as a medicine for hyperlipemia and the substanceis not expectable as a preferable material from the safety point of viewowing to its new physiological action.

No proposal has been made on medicinal compositions containing thecompound of the present invention to improve the absorption through thedigestive tracts by reducing the contact with the components in the bileor pancreatic juice.

The object of the present invention is to provide medicinal compositionscontaining the compound of the present invention.

Another object of the present invention is to provide medicinalcompositions containing the compound of the present invention andeffective for improving the absorption through the digestive tracts byreducing the contact of the compound with the components in the bile orpancreatic juice in the case of peroral administration.

DISCLOSURE OF THE INVENTION

The present invention provides medicinal compositions containing one ormore compounds selected from the compounds represented by the followingformula (I), salts of these compounds, solvates of these compounds andsolvates of these salts (hereinafter collectively called as “thecompounds of the present invention” in some cases) and being capable ofreducing the contact of the compounds with the components in the bile orpancreatic juice.

[in the Formula (I),

R¹ is hydrogen atom, fluorine atom, chlorine atom, bromine atom,hydroxyl group, amino group, nitro group, a C₁-C₈ alkyl group or a C₁-C₈alkoxy group,

L is direct bond or a C₁-C₄ alkylene group,

R² is fluorine atom, chlorine atom, bromine atom, hydroxyl group, aminogroup, a C₁-C₈ alkoxy group, carboxyl group, a C₁-C₈ alkoxycarbonylgroup, an aryloxycarbonyl group, an aralkoxycarbonyl group, carbamoylgroup (the nitrogen atom constituting the carbamoyl group may besubstituted with mono- or di-C₁-C₈ alkyl group or may be the nitrogenatom of an amino acid), a C₁-C₈ alkylcarbonyl group, a C₁-C₈alkylsulfenyl group, a C₁-C₈ alkylsulfinyl group, a C₁-C₈ alkylsulfonylgroup, a mono- or di-C₁-C₈ alkylamino group, a mono- or di-C₁-C₈alkylaminosulfonyl group, sulfo group, phosphono group,bis(hydroxycarbonyl)methyl group, a bis(alkoxycarbonyl)methyl group or5-tetrazolyl group,

R³ is hydrogen atom, fluorine atom, chlorine atom, bromine atom,hydroxyl group, amino group, nitro group, a C₁-C₈ alkyl group, a C₁-C₈alkoxy group, carboxyl group or a C₁-C₈ alkoxycarbonyl group,

X is a group of the formulas —O—, —S—, —SO—, —SO₂—, —NH—CO—NH—, —N(R⁴)—,—CO—N(R⁵)—, —N(R⁵)—CO—, —N(R⁵)—SO₂— or —SO₂—N(R⁵)— (in the formulas,

R⁴ is hydrogen atom, a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkylcarbonyl group,a C₁-C₁₀ alkylsulfonyl group, a C₃-C₈ cycloalkyl group or an aryl group,

R⁵ is hydrogen atom, a C₁-C₁₀ alkyl group, a C₃-C₈ cycloalkyl group oran aryl group (the alkyl groups of R⁴ and R⁵ may be substituted with anaryl group, hydroxyl group, amino group, a halogen atom, a C₁-C₈ alkoxygroup, carboxyl group, a C₁-C₈ alkoxycarbonyl group, an aryloxycarbonylgroup, an aralkoxycarbonyl group, carbamoyl group or 5-tetrazolylgroup),

Y is a C₄-C₈ cycloalkyl group (in the above ring system, the methylenegroup may be replaced with carbonyl group and the ring system may besubstituted with fluorine atom, chlorine atom, bromine atom, hydroxylgroup, amino group, a C₁-C₈ alkyl group, a C₁-C₈ alkoxy group, carbamoylgroup, a C₁-C₈ alkoxycarbonyl group, carboxyl group, an aminoalkylgroup, a mono- or di-alkylamino group or a mono- or di-alkylaminoalkylgroup), or a 5- to 8-membered ring group of the following formulas I-1or I-2

 (in the formulas I-1 and I-2,

the methylene group of each ring system may be replaced with carbonylgroup and unsaturated bond may be present in the ring,

R⁶ is hydrogen atom, fluorine atom, chlorine atom, bromine atom,hydroxyl group, amino group, nitro group, a C₁-C₈ alkyl group or a C₁-C₈alkoxy group,

W is C—H or nitrogen atom (W is not nitrogen atom when the ring is a5-membered ring),

Z is hydrogen atom, a C₁-C₁₀ alkyl group (the alkyl group may besubstituted with hydroxyl group (excluding the case of C₁ alkyl group),amino group, a C₁-C₈ alkoxy group (excluding the case of C₁ alkylgroup), carboxyl group, a C₁-C₈ alkoxycarbonyl group, an aryloxycarbonylgroup or an aralkoxycarbonyl group), a C₁-C₈ alkylcarbonyl group, anarylcarbonyl group, an aralkylcarbonyl group, amidino group or a groupof the following formula I-3

 (in the Formula I-3,

R⁷ is a C₁-C₈ alkyl group (the alkyl group may be substituted withhydroxyl group or a C₁-C₈ alkoxy group), an aralkyl group or an arylgroup),

m is an integer of from 1 to 3, and

n is an integer of from 0 to 3 (when n is 0 or 1, W is not nitrogenatom)].

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is explained in more detail by the followingdescription.

In the above definition of the substituent of the compound of thegeneral formula (I) of the present invention, the “C₁-C₈ alkyl group”means a straight or branched carbon chain having 1 to 8 carbon atoms,for example, methyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, tert-butyl group, pentyl group, neopentylgroup, isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexylgroup, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutylgroup, 2-ethylbutyl group, isoheptyl group, octyl group or isooctylgroup, preferably a group having a carbon number of from 1 to 4,especially preferably methyl group or ethyl group.

The “C₁-C₈ alkoxy group” means an alkoxy group having a carbon number offrom 1 to 8, concretely methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, pentyloxy group, neopentyloxy group, tert-pentyloxygroup, 2-methylbutoxy group, hexyloxy group, isohexyloxy group,heptyloxy group, isoheptyloxy group, octyloxy group, isooctyloxy group,etc., preferably a group having a carbon number of from 1 to 4,especially preferably methoxy group or ethoxy group.

The “C₁-C₄ alkylene” means a straight-chain alkylene having a carbonnumber of from 1 to 4 and is methylene, ethylene, propylene or butylene.

The “C₁-C₈ alkoxycarbonyl group” means methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group,tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonylgroup, neopentyloxycarbonyl group, hexyloxycarbonyl group,heptyloxycarbonyl group, octyloxycarbonyl group, etc., preferablymethoxycarbonyl group, ethoxycarbonyl group or tert-butoxycarbonylgroup, more preferably methoxycarbonyl group.

The “aryloxycarbonyl group” means phenoxycarbonyl group,naphthyloxycarbonyl group, 4-methylphenoxycarbonyl group,3-chlorophenoxycarbonyl group, 4-methoxyphenoxycarbonyl group, etc.,preferably phenoxycarbonyl group.

The “aralkoxycarbonyl group” means benzyloxycarbonyl group,4-methoxybenzyloxycarbonyl group, 3-trifluoromethylbenzyloxycarbonylgroup, etc., preferably benzyloxycarbonyl group.

The “amino acid” means natural or non-natural commercially availableamino acids, preferably glycine, alanine or β-alanine, more preferablyglycine.

The “C₁-C₈ alkylcarbonyl group” means a carbonyl group having straightor branched carbon chain having a carbon number of from 1 to 8, e.g.formyl group, acetyl group, propionyl group, butyryl group, isobutyrylgroup, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group,heptanoyl group and octanoyl group, preferably a carbonyl group having acarbon number of from 1 to 4, more preferably acetyl group or propionylgroup.

The “C₁-C₈ alkylsulfenyl group” means an alkylsulfenyl group having acarbon number of from 1 to 8, concretely methylthio group, ethylthiogroup, butylthio group, isobutylthio group, pentylthio group, hexylthiogroup, heptylthio group, octylthio group, etc., preferably methylthiogroup.

The “C₁-C₈ alkylsulfinyl group” means an alkylsulfinyl group having acarbon number of from 1 to 8, concretely methylsulfinyl group,ethylsulfinyl group, butylsulfinyl group, hexylsulfinyl group,octylsulfinyl group, etc., preferably methylsulfinyl group.

The “C₁-C₈ alkylsulfonyl group” means an alkylsulfonyl group having acarbon number of from 1 to 8, concretely methylsulfonyl group,ethylsulfonyl group, butylsulfonyl group, hexylsulfonyl group,octylsulfonyl group, etc., preferably methylsulfonyl group.

The “mono- or di-C₁-C₈ alkylamino group” means methylamino group,dimethylamino group, ethylamino group, propylamino group, diethylaminogroup, isopropylamino group, dilsopropylamino group, dibutylamino group,butylamino group, isobutylamino group, sec-butylamino group,tert-butylamino group, pentylamino group, hexylamino group, heptylaminogroup, octylamino group, etc., preferably methylamino group,dimethylamino group, ethylamino group, diethylamino group or propylaminogroup, more preferably methylamino group or dimethylamino group.

The “mono- or di-C₁-C₈ alkylaminosulfonyl group” meansmethylaminosulfonyl group, dimethylaminosulfonyl group,ethylaminosulfonyl group, propylaminosulfonyl group,diethylaminosulfonyl group, isopropylaminosulfonyl group,diisopropylaminosulfonyl group, dibutylaminosulfonyl group,butylaminosulfonyl group, isobutylaminosulfonyl group,sec-butylaminosulfonyl group, tert-butylaminosulfonyl group,pentylaminosulfonyl group, hexylaminosulfonyl group, heptylaminosulfonylgroup, octylaminosulfonyl group, etc., preferably methylaminosulfonylgroup, dimethylaminosulfonyl group, ethylaminosulfonyl group,diethylaminosulfonyl group or propylaminosulfonyl group, more preferablymethylaminosulfonyl group or dimethylaminosulfonyl group.

The “bis(alkoxycarbonyl)methyl group” means bis(methoxycarbonyl)methylgroup, bis(ethoxycarbonyl)methyl group, etc., preferablybis(methoxycarbonyl)methyl group.

The “C₁-C₁₀ alkyl group” means a straight or branched carbon chainhaving a carbon number of from 1 to 10, e.g. methyl group, ethyl group,propyl group, isopropyl group, butyl group, isobutyl group, tert-butylgroup, pentyl group, neopentyl group, isopentyl group,1,2-dimethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutylgroup, 2,2-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group,heptyl group, isoheptyl group, 1-methylhexyl group, 2-methylhexyl group,octyl group, 2-ethylhexyl group, nonyl group, decyl group, 1-methylnonylgroup, etc., preferably a group having a carbon number of from 1 to 4,especially preferably methyl group or ethyl group.

The “C₁-C₁₀ alkylcarbonyl group” means a carbonyl group having straightor branched carbon chain having a carbon number of from 1 to 10, e.g.formyl group, acetyl group, propionyl group, butyryl group, isobutyrylgroup, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group,heptanoyl group, octanoyl group, nonanoyl group, decanoyl group, etc.,preferably a group having a carbon number of from 1 to 4, morepreferably acetyl group or propionyl group.

The “C₁-C₁₀ alkylsulfonyl group” means an alkylsulfonyl group having acarbon number of from 1 to 10, concretely methylsulfonyl group,ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group,butylsulfonyl group, isobutylsulfonyl group, pentylsulfonyl group,isopentylsulfonyl group, neopentylsulfonyl group, hexylsulfonyl group,heptylsulfonyl group, octylsulfonyl group, nonylsulfonyl group,decylsulfonyl group, etc., preferably a group having a carbon number offrom 1 to 4, especially preferably methylsulfonyl group or ethylsulfonylgroup.

The “C₃-C₈ cycloalkyl group” means a cycloalkyl group having a carbonnumber of from 3 to 8, concretely cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctylgroup, preferably cyclopropyl group. The “aryl group” means ahydrocarbon ring aryl group such as phenyl group and naphthyl group or aheteroaryl group such as pyridyl group and furyl group, preferablyphenyl group.

The “C₄-C₈ cycloalkyl group” means a cycloalkyl group having a carbonnumber of from 4 to 8, concretely cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group or cyclooctyl group, preferablycyclopentyl group or cyclohexyl group.

The “aminoalkyl group” means a straight-chain alkyl group having acarbon number of from 1 to 8, concretely 8-aminooctyl group,6-aminohexyl group, 4-aminobutyl group, 2-aminoethyl group oraminomethyl group, preferably 2-aminoethyl group or aminomethyl group.

The “mono- or di-alkylamino group” means methylamino group,dimethylamino group, ethylamino group, propylamino group, diethylaminogroup, isopropylamino group, diisopropylamino group, dibutylamino group,butylamino group, isobutylamino group, sec-butylamino group,tert-butylamino group, etc., preferably methylamino group, dimethylaminogroup, ethylamino group, diethylamino group, isopropylamino group ordiisopropylamino group, more preferably ethylamino group, diethylaminogroup or isopropylamino group.

The “mono- or di-alkylaminoalkyl group” means methylaminoethyl group,dimethylaminoethyl group, ethylaminoethyl group, methylaminopropylgroup, dimethylaminopropyl group, ethylaminopropyl group,diethylaminopropyl group, methylaminobutyl group, dimethylaminobutylgroup, etc., preferably methylaminoethyl group, dimethylaminoethyl groupor ethylaminoethyl group.

The “C₁-C₁₀ alkyl group” bonding to a nitrogen atom as the group Z meansa straight or branched carbon chain having a carbon number of from 1 to10, e.g. methyl group, ethyl group, propyl group, isopropyl group, butylgroup, isobutyl group, tert-butyl group, pentyl group, neopentyl group,isopentyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group,1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group,2-ethylbutyl group, heptyl group, isoheptyl group, 1-methylhexyl group,2-methylhexyl group, octyl group, 2-ethylhexyl group, nonyl group, decylgroup, 1-methylnonyl group, etc., preferably a group having a carbonnumber of from 1 to 4, especially preferably isopropyl group or propylgroup.

The “arylcarbonyl group” means benzoyl group, 4-methoxybenzoyl group,3-trifluoromethylbenzoyl group, etc., preferably benzoyl group.

The “aralkylcarbonyl group” is concretely benzylcarbonyl group,phenethylcarbonyl group, phenylpropylcarbonyl group,1-naphthylmethylcarbonyl group, 2-naphthylmethylcarbonyl group, etc.,preferably benzylcarbonyl group.

The “aralkyl group” is concretely benzyl group, phenethyl group,phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group,etc., preferably benzyl group.

There is no particular restriction on the kind of the salt of thecompound of the present invention provided that the salt ispharmacologically permissible, and the examples of the salts arehydrochloric acid salt, sulfuric acid salt, nitric acid salt, phosphoricacid salt, tartaric acid salt, maleic acid salt, succinic acid salt,malonic acid salt, glutaric acid salt, malic acid salt, adipic acidsalt, acetic acid salt, propionic acid salt, hydrobromic acid salt,hydroiodic acid salt, methanesulfonic acid salt, 2-hydroxysulfonic acidsalt and p-toluenesulfonic acid salt.

There is no particular restriction on the kind of the solvate of thecompound of the present invention or its salt provided that the solvateis pharmacologically permissible, and hydrate, etc., are preferableexamples.

Representative processes for the production of the compound of thepresent invention expressed by the formula (I) are described as follows.

When the starting compounds or reaction intermediates have substituentspossible to exert influence on the reaction such as hydroxyl group,amino group and carboxyl group, the etherification reaction is carriedout preferably after properly protecting such functional groups and theprotecting group is eliminated after the reaction. Any protecting groupordinarily used for the protection of individual substituent can be usedas the protecting group provided that the substituent exerts no adverseinfluence on the other part of the molecule during the protecting anddeprotecting steps. The protecting groups for hydroxyl group aretrialkylsilyl group, C₁-C₄ alkoxymethyl group, tetrahydropyranyl group,acyl group, C₁-C₄ alkoxycarbonyl group, etc., the protecting groups foramino group are C₁-C₄ alkoxycarbonyl group, benzyloxycarbonyl group,acyl group, etc., and the protecting groups for carboxyl group are C₁-C₄alkyl group, etc. The deprotection reaction can be performed accordingto a process usually adopted to the protecting group.

The compounds containing oxygen atom as the group X among the nitrilecompound used as a precursor of the compound of the present inventionexpressed by the formula (I) can be synthesized e.g. by the reactionshown by the following reaction formula (a-1).

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), Y¹, is a substituent Y defined inthe formula (I) except for the group having a substituent Z of thestructure expressed by the formula I-3 on the group Y, and R⁸ ishydrogen atom, fluorine atom, chlorine atom, bromine atom, hydroxylgroup (or its protected group), amino group (or its protected group) orC₁-C₈ alkoxy group].

Namely, a nitrile compound as a precursor of the compound of the presentinvention can be produced according to the above reaction formula (a-1)by mixing a biphenylalkyl bromide compound used as a starting rawmaterial with an alcohol of formula Y¹—(CH₂)_(n)—OH in the presence of abase.

The compound containing oxygen atom as the group X among the nitrilecompounds used as the precursor of the compound of the present inventionexpressed by the formula (I) can be synthesized by the reactionexpressed by the following reaction formula (a-2).

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those of the formula (I), and Y¹ is a substituent Y defined in theformula (I) except for the group having a substituent Z of the structureexpressed by the formula I-3 on the group Y].

Namely, the nitrile compound used as a precursor of the compound of thepresent invention can be synthesized by mixing 3-bromo-3-iodophenylalkylbromide used as a starting raw material with an alcohol expressed by theformula Y¹—(CH₂)_(n)—OH in the presence of a base to form a3-bromo-3-iodophenylalkyl ether compound, introducing a substituent—L—COOMe into the obtained ether compound by monocarbonylation ormonoalkylation and subjecting the produced 3-bromophenylalkyl ether tocoupling reaction with a cyanophenylboronic acid derivative.

The etherification reaction expressed in the 1st stage of the reactionformulas (a-1) and (a-2) is carried out by using an aliphatic ether suchas tetrahydrofuran and diethyl ether, an aprotic hydrocarbon such asbenzene and toluene, an aprotic polar solvent such as DMF and HMPA ortheir mixture. The base to be used in the reaction is a metal oxide suchas barium oxide and zinc oxide, a metal hydroxide such as sodiumhydroxide and potassium hydroxide, metal hydride such as sodium hydride,etc. The reaction proceeds usually by stirring at 0 to 100° C. for 3 to72 hours. Preferably, the reaction is carried out in an anhydrousaliphatic ether such as THF and ether using sodium hydride at 20 to 80°C. for 8 to 36 hours.

The 2nd stage of the reaction formula (a-2) comprising the reaction tointroduce a substituent —L—COOMe into the ether compound can be carriedout by the following reactions (i) and (ii).

(i) Monocarbonylation reaction by the introduction of carbon monoxide(when L is a bond): The ether compound obtained by the 1st stage of thereaction formula (a-1) is dissolved in methanol, a bivalent palladiumcatalyst, a base such as a tertiary amine, e.g. triethylamine and asnecessary a phosphine ligand such as triphenyl phosphine are added tothe solution and the mixture is stirred in carbon monoxide atmosphere atroom temperature or under heating for 3 to 48 hours to convert theiodine atom into methoxycarbonyl group. Preferably, the catalyst isbistriphenylphosphine palladium chloride or palladium acetate, the baseis diisopropylethylamine or tributylaluminum and the reaction is carriedout at 60 to 80° C. for 12 to 36 hours.

(ii) Monoalkylation reaction with an organozinc reagent (when L is aC₁-C₄ alkylene group): The ether compound obtained by the 1st stage ofthe reaction formula (a-1) is dissolved together with a zero-valentpalladium catalyst such as tetrakistriphenylphosphine palladium into asolvent such as THF, DMF, benzene, toluene or their mixture, a THFsolution of an alkylzinc reaction agent expressed by the formulaI—Zn—L—COOMe is added to the solution and the mixture is stirred incarbon monoxide atmosphere at room temperature or under heating for 3 to48 hours to convert the iodine into an alkyl group. Preferably, thereaction is carried out at 20-80° C. for 6 to 36 hours usingtetrakistriphenylphosphine palladium as the catalyst and THF as thesolvent.

The biphenylation reaction constituting the 3rd stage of the reactionformula (a-2) can be performed by reacting a monohalogenated compoundwith cyanophenyl boronic acid in the presence of a palladium catalyst.The reaction proceeds usually by stirring the monohalogenated compoundobtained by the 2nd stage of the reaction formula (a-2), a bivalentpalladium catalyst such as palladium acetate and further a base such astriethylamine and a triaryl phosphine in DMF under heating to obtain theobjective cyanobiphenyl compound. The reaction is preferably carried outat 60 to 100° C. for 2 to 24 hours.

The compound having nitrogen atom as the group X among the nitrilecompounds constituting the precursor of the compound of the presentinvention described by the formula (I) can be synthesized e.g. by thereaction of the following reaction formula (b-1) or (b-2).

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), R⁹ is fluorine atom, chlorineatom, bromine atom, hydroxyl group (or its protected group), amino group(or its protected group), a C₁-C₈ alkoxy group or methoxycarbonyl groupamong the substituents R² defined in the formula (I), Y¹ is asubstituent Y defined in the formula (I) except for the group having asubstituent Z of the structure expressed by the formula I-3 on the groupY, R¹⁰ is the substituent R⁴ defined in the formula (I) excludinghydrogen atom and aryl group, and E is an eliminable group such aschlorine, bromine, iodine, acyloxy group or sulfonyloxy group].

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), R⁹ is fluorine atom, chlorineatom, bromine atom, hydroxyl group (or its protected group), amino group(or its protected group), a C₁-C₈ alkoxy group or methoxycarbonyl groupamong the substituents R² defined in the formula (I), Y¹ is asubstituent Y defined in the formula (I) except for the group having asubstituent Z of the structure expressed by the formula I-3 on the groupY, Ar is an aryl group, and E is an eliminable group such as chlorine,bromine, iodine, acyloxy group or sulfonyloxy group].

The N-alkylation reaction shown by the reaction formulas (b-1) and (b-2)can be carried out under known alkylation reaction conditions.Concretely, a secondary amine compound constituting the compound of thepresent invention is produced by reacting a biphenylalkyl bromide usedas a raw material with an amine of formula Y¹—(CH₂)_(n)—NH₂ in thepresence of an inorganic salt such as potassium carbonate or an aminesuch as a tertiary amine acting as a base and the obtained secondaryamine compound can be converted to the tertiary amine as the compound ofthe present invention by reacting with an alkylation agent expressed bythe formula R⁴—E. The reaction is usually carried out by mixing thealkylation agent and the amine at an arbitrary ratio in a proper solventand by stirring the mixture under cooling, at room temperature or underheating for 1 to 96 hours. The reaction is usually performed by using aninorganic salt such as potassium carbonate and sodium carbonate or anorganic tertiary amine such as triethylamine and pyridine as the baseand an alcohol such as methanol and ethanol, a hydrocarbon such asbenzene and toluene, a solvent inert to the reaction such as THF,dioxane, acetonitrile DMF and DMSO or their mixture as the solvent at an(alkylation agent):(amine) ratio of 1:10 to 10:1. Preferably, the ratioof the alkylation agent to the amine is set to 1:5 to 1:1 and thereaction is carried out at room temperature or under heating for 2 to 24hours.

The compound containing sulfur atom as the group X among the nitrilecompounds constituting a precursor of the compound of the presentinvention expressed by the formula (I) can be synthesized e.g. by thereaction shown by the following reaction formula (c-1) or (c-2).

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), R⁹ is fluorine atom, chlorineatom, bromine atom, hydroxyl group (or its protected group), amino group(or its protected group), a C₁-C₈ alkoxy group or methoxycarbonyl groupamong the substituents R² defined in the formula (I), Y¹ is asubstituent Y defined in the formula (I) except for the group having asubstituent Z of the structure expressed by the formula I-3 on the groupY, and E is an eliminable group such as chlorine, bromine, iodine orsulfonato group].

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), R⁹ is fluorine atom, chlorineatom, bromine atom, hydroxyl group (or its protected group), amino group(or its protected group), a C₁-C₈ alkoxy group or methoxycarbonyl groupamong the substituents R² defined in the formula (I), Y¹ is asubstituent Y defined in the formula (I) except for the group having asubstituent Z of the structure expressed by the formula I-3 on the groupY, and E is an eliminable group such as chlorine, bromine, iodine orsulfonato group].

The thioetherification reaction expressed by the reaction formulas (c-1)and (c-2) can be carried out under known reaction conditions. Usually,the reaction is carried out by mixing an alkyl halide with a thiol at anarbitrary ratio in a proper solvent in the presence of a base such assodium hydroxide or ammonia and stirring the mixture under cooling, atroom temperature or under heating for 30 minutes to 96 hours. A solventfree from adverse effect on the reaction such as water, ethanol, DMF ortoluene is used as the reaction solvent and the base is sodiumhydroxide, ammonia, cesium carbonate, etc. The reaction is preferablycarried out by mixing the alkyl halide with the thiol at a ratio of 1:5to 5:1 and stirring the mixture at room temperature or under heating for30 minutes to 24 hours.

A compound having sulfoxide group or sulfone group as the group X amongthe compounds expressed by the formula (I) can be synthesized by theoxidation reaction of the obtained sulfide compound according to thefollowing reaction formula (d).

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), R⁹ is fluorine atom, chlorineatom, bromine atom, hydroxyl group (or its protected group), amino group(or its protected group), a C₁-C₈ alkoxy group or methoxycarbonyl groupamong the substituents R² defined in the formula (I), and Y¹ is asubstituent Y defined in the formula (I) except for the group having asubstituent Z of the structure expressed by the formula I-3 on the groupY].

The oxidation reaction expressed by the reaction formula (d) can becarried out by the method described in the Experimental Chemistry Course(4th edition), 24, Organic Syntheses VI—Hetero-Element. Typical MetalCompound-, p.350-373 edited by the Chemical Society of Japan. Thereaction is usually carried out by stirring a sulfide or a sulfoxide inwater or an alcohol such as methanol using hydrogen peroxide, peraceticacid, meta-periodic acid salt, m-chloroperbenzoic acid, etc., as anoxidizing agent under cooling, at room temperature or under heating for30 minutes to 24 hours. Preferably, the sulfoxide is produced at 0-20°C. in 30 to 12 hours and the sulfone is produced at 0-80° C. in 1 to 12hours.

The compound containing amide bond as the group X among the nitrilecompounds constituting a precursor of the compound of the presentinvention expressed by the formula (I) can be synthesized e.g. by thereaction shown by the following reaction formula (e-1) or (e-2).

[in the reaction formula, the definitions of R¹, R³, R⁵, L, m and n aresame as those described in the formula (I), R⁹ is fluorine atom,chlorine atom, bromine atom, hydroxyl group (or its protected group),amino group (or its protected group), a C₁-C₈ alkoxy group ormethoxycarbonyl group among the substituents R² defined in the formula(I), Y¹ is a substituent Y defined in the formula (I) except for thegroup having a substituent Z of the structure expressed by the formulaI-3 on the group Y, and G is a group such as halogen, acyloxy group,p-nitrophenoxy group and hydroxyl group].

[in the reaction formula, the definitions of R¹, R³, R⁵, L, m and n aresame as those described in the formula (I), R⁹ is fluorine atom,chlorine atom, bromine atom, hydroxyl group (or its protected group),amino group (or its protected group), a C₁-C₈ alkoxy group ormethoxycarbonyl group among the substituents R² defined in the formula(I), Y¹ is a substituent Y defined in the formula (I) except for thegroup having a substituent Z of the structure expressed by the formulaI-3 on the group Y, and G is a group such as halogen, acyloxy group,p-nitrophenoxy group and hydroxyl group].

The reaction of the above reaction formula (e-1) or (e-2) can be carriedout under the known amidation reaction conditions. An amide compound isproduced usually by mixing an active derivative of a carboxylic acidwith an amine compound in a proper solvent in the presence of a base,followed with acylating the compound. The active derivative ofcarboxylic acid is an acid halide, an anhydride of a mixed acid, anactive ester of p-nitrophenol, etc., and the reaction is carried outunder cooling or at room temperature for 30 minutes to 24 hours. Thereaction is preferably carried out by using a tertiary amine such astriethylamine as the base in a halogenated hydrocarbon such asdichloromethane, an aliphatic ether such as THF and diethyl ether, asolvent such as acetonitrile and DMF or their mixture at 0 to 20° C. for1 to 18 hours.

The amide compound is producible also by the condensation reaction of anamine with a carboxylic acid in the presence of a condensing agent suchas carbodiimide. In this case, the suitable solvent is DMF and ahalogenated hydrocarbon such as chloroform and the condensing agent ispreferably N,N-dicyclohexylcarbodiimide,1-ethyl-(3-(N,N-dimethylamino)propyl)carbodiimide, carbonyl diimidazole,diphenylphosphoryl azide or diethylphosphoryl cyanide. The reaction iscarried out usually under cooling or at room temperature for,2 to 48hours.

The compound containing sulfonamide structure as the group X among thenitrile compounds constituting a precursor of the compound of thepresent invention expressed by the formula (I) can be synthesized e.g.by the reaction shown by the following reaction formula (f-1) or (f-2).

[in the reaction formula, the definitions of R¹, R³, R⁵, L, m and n aresame as those described in the formula (I), R⁹ is fluorine atom,chlorine atom, bromine atom, hydroxyl group (or its protected group),amino group (or its protected group), a C₁-C₈ alkoxy group ormethoxycarbonyl group among the substituents R² defined in the formula(I), and Y¹ is a substituent Y defined in the formula (I) except for thegroup having a substituent Z of the structure expressed by the formulaI-3 on the group Y].

[in the reaction formula, the definitions of R¹, R³, R⁵, L, m and n aresame as those described in the formula (I), R⁹ is fluorine atom,chlorine atom, bromine atom, hydroxyl group (or its protected group),amino group (or its protected group), a C₁-C₈ alkoxy group ormethoxycarbonyl group among the substituents R² defined in the formula(I), and Y¹ is a substituent Y defined in the formula (I) except for thegroup having a substituent Z of the structure expressed by the formulaI-3 on the group Y].

The reaction expressed by the reaction formulas (f-1) and (f-2) can becarried out by reacting an amine with an active derivative of a sulfonicacid in a proper solvent in the presence of a base to obtain theobjective sulfonamide compound. The active derivative of sulfonic acidis preferably a sulfonyl halide and the reaction is carried out by usinga tertiary amine such as triethylamine as the base in a halogenatedhydrocarbon such as dichloromethane, an aliphatic ether such as THF ordiethyl ether, a solvent such as acetonitrile or DMF or their mixture at0 to 20° C. for 1 to 24 hours.

The compound containing urea structure as the group X among the nitrilecompounds constituting a precursor of the compound of the presentinvention expressed by the formula (I) can be synthesized e.g. by thereaction shown by the following reaction formula (g).

[in the reaction formula, the definitions of R¹, R³, L, m and n are sameas those described in the formula (I), R⁹ is fluorine atom, chlorineatom, bromine atom, hydroxyl group (or its protected group), amino group(or its protected group), a C₁-C₈ alkoxy group or methoxycarbonyl groupamong the substituents R² defined in the formula (I), and Y¹ is asubstituent Y defined in the formula (I) except for the group having asubstituent Z of the structure expressed by the formula I-3 on the groupY].

Namely, the compound having urea structure as the group X can beproduced by reacting an amine as a starting raw material with anisocyanate derivative in a proper solvent under cooling or heating. Thesolvent to be used in the reaction is DMF, THF, dioxane, dichloroethane,chloroform, acetonitrile, DMSO, benzene, toluene, etc.

The nitrile compound constituting a precursor of the compound of thepresent invention and produced by the above reaction formulas (a-1),(a-2), (b-1), (b-2), (c-1), (c-2), (d), (e-1), (e-2), (f-1), (f-2) and(g) can be converted to a benzamidine derivative which is a compound ofthe present invention by the amidination reaction shown by the followingreaction formula (h).

[in the reaction formula, the definitions of R¹, R³, L, X, m and n aresame as those described in the formula (I), Y¹ is a substituent Ydefined in the formula (I) except for the group having a substituent Zof the structure expressed by the formula I-3 on the group Y, R⁹ isfluorine atom, chlorine atom, bromine atom, hydroxyl group (or itsprotected group), amino group (or its protected group), a C₁-C₈ alkoxygroup or methoxycarbonyl group among the substituents R² defined in theformula (I), and R¹¹ is a C₁-C₄ alkyl group].

The amidination reaction is carried out under the reaction conditionsshown by the following description (iii) or (iv).

(iii) The amidination reaction through imidation process using analcohol solution of a hydrogen halide: The reaction to produce animidate from a nitrile and an alcohol proceeds e.g. by the stirring ofan alkoxymethylphenyl benzonitrile compound in the form of a solutiondissolved in a C₁-C₄ alcohol (R¹¹OH) containing a hydrogen halide suchas hydrogen chloride or hydrogen bromide. The reaction is usuallycarried out at −20 to +30° C. for 12 to 96 hours, preferably in amethanol or ethanol solution of hydrogen chloride at −10 to +30° C. for24 to 72 hours. The reaction of an imidate with ammonia proceeds to forma benzamidine derivative (I) as the compound of the present invention bystirring an imidate in a solvent containing ammonia or an amine such ashydroxylamine, hydrazine or a carbamic acid ester and selected from aC₁-C₄ alcohol such as methanol and ethanol, an aliphatic ether solventsuch as diethyl ether, a halogenated hydrocarbon solvent such asdichloromethane and chloroform or their mixture. The reaction is usuallycarried out at −10 to +50° C. for 1 to 48 hours, preferably in methanolor ethanol at 0 to 30° C. for 2 to 12 hours.

(iv) The amidination reaction through an imidate prepared by directlyblowing a hydrogen halide: The reaction of a nitrile with an alcoholproceeds e.g. by dissolving a nitrile in an aliphatic ether such asdiethyl ether, a halogenated hydrocarbon such as chloroform or anaprotic solvent such as benzene, adding an equivalent or excess amountof C₁-C₄ alcohol (R¹¹OH) to the solution, passing a hydrogen halide suchas hydrogen chloride and hydrogen bromide through the mixture understirring at −30 to 0° C. for 30 minutes to 6 hours, stopping the supplyof the hydrogen halide and continuing the stirring at 0 to 50° C. for 3to 96 hours. Preferably, hydrogen chloride is passed through ahalogenated hydrocarbon containing equivalent or excess amount ofmethanol or ethanol under stirring at −10 to 0° C. for 1 to 3 hours, thesupply of the hydrogen chloride is stopped and the product is stirred at10 to 40° C. for 8 to 24 hours. The imidate produced by the aboveprocess can be converted to a benzamidine derivative (I) as the compoundof the present invention by stirring in a solvent containing ammonia oran amine such as hydroxylamine, hydrazine or a carbamic acid ester andselected from a C₁-C₄ alcohol solvent such as methanol or ethanol, analiphatic ether solvent such as diethyl ether, a halogenated hydrocarbonsolvent such as chloroform or their mixture. The reaction is usuallycarried out at −20 to +50° C. for 1 to 48 hours, preferably in ethanolsaturated with ammonia at 0 to 30° C. for 2 to 12 hours.

The compound having the substituent Y containing a substituent Z havingthe structure expressed by the formula I-3 among the compounds of thepresent invention expressed by the formula (I) can be produced byproducing a benzamidine compound having a secondary amino group in thesubstituent Y by the reaction expressed by the above reaction formula(h), followed by the imidoylation reaction of the product according tothe following reaction formulas (j-1) and (j-2).

[in the reaction formula, the definitions of R¹, R³, R⁶, L, W, X, Z, mand n are same as those described in the formula (I), and R⁹ is fluorineatom, chlorine atom, bromine atom, hydroxyl group (or its protectedgroup), amino group (or its protected group), a C₁-C₈ alkoxy group ormethoxycarbonyl group among the substituents R² defined in the formula(I)].

[in the reaction formula, the definitions of R¹, R³, R⁶, L, W, X, Z, mand n are same as those described in the formula (I), and R⁹ is fluorineatom, chlorine atom, bromine atom, hydroxyl group (or its protectedgroup), amino group (or its protected group), a C₁-C₈ alkoxy group ormethoxycarbonyl group among the substituents R² defined in the formula(I)].

The imidoylation reaction proceeds by mixing and stirring a benzamidinecompound having a secondary amino group in the substituent Y togetherwith an equivalent or excess amount of an imidate in water, a C₁-C₄alcohol such as methanol or ethanol, an aliphatic ether such as diethylether, a halogenated hydrocarbon such as chloroform, a polar solventsuch as DMF or DMSO or their mixture in the presence of a base. Thereaction is usually carried out for 1 to 24 hours at room temperature.The base to be used in the above reaction is N-methylmorpholine,triethylamine, diusopropylethylamine, sodium hydroxide, potassiumhydroxide, etc.

The compound having carboxyl group as the group R² among the compoundsexpressed by the formula (I) can be produced by the ester hydrolysis ofa compound having methoxycarbonyl group as the group R⁹ among thebenzamidine compounds produced by the above reaction formulas (h), (j-1)and (j-2). The hydrolysis reaction can be carried out under basiccondition, acidic condition or neutral condition at need. The base to beused in the reaction under basic condition is sodium hydroxide,potassium hydroxide, lithium hydroxide, barium hydroxide, etc., the acidfor the acidic reaction condition is hydrochloric acid, sulfuric acid, aLewis acid such as boron trichloride, trifluoroacetic acid,p-toluenesulfonic acid, etc., and the examples of the substances to beused in the reaction under neutral condition are halogen ions such aslithium iodide and lithium bromide, alkali metal salts of a thiol andselenol, iodotrimethylsilane and enzymes such as an esterase. Thesolvent for the reaction is a polar solvent such as water, alcohol,acetone, dioxane, THF, DMF and DMSO or their mixture. The reaction iscarried out usually at room temperature or under heating for 2 to 96hours. The preferable conditions of the reaction temperature andreaction time, etc., are dependent on the reaction condition andproperly selected according to conventional method.

The carboxyl group of the compound having carboxyl group as thesubstituent R² and produced by this process can be converted to otherester group by the following methods of (v), (vi) and (vii).

(v) Conversion of carboxyl group into an alkoxycarbonyl group: Thecarboxyl group of a compound having carboxyl group as the substituent R²among the compounds expressed by the formula (I) can be converted intoan alkoxycarbonyl group by reacting the compound with equivalent orexcess amount of an alkylation agent (e.g. acyloxymethyl chloride suchas acetoxymethyl chloride and pivaloyloxymethyl chloride, allyl chlorideand benzyl chloride) in a halogenated hydrocarbon such asdichloromethane, an aliphatic ether such as THF, an aprotic polarsolvent such as DMF or their mixture in the presence of a tertiary aminesuch as triethylamine and diusopropylethylamine at −10 to +80° C. for 1to 48 hours. The reaction is preferably carried out by using equivalentor small excess amount of the alkylation agent in the presence ofdiusopropylethylamine at 20 to 60° C. for 2 to 24 hours.

(vi) Conversion of carboxyl group into an aralkoxycarbonyl group: Thecarboxyl group of a compound having carboxyl group as the substituent R²among the compounds expressed by the formula (I) can be converted intoan aralkoxycarbonyl group by reacting the compound with equivalent orexcess amount of an alcohol such as benzyl alcohol in a halogenatedhydrocarbon such as dichloromethane in the presence of an acid catalystsuch as hydrochloric acid, sulfuric acid and sulfonic acid. The reactionis carried out usually at room temperature or under heating for 1 to 72hours, preferably by using equivalent or small excess amount of analcohol in the presence of diisopropylethylamine at 20 to 60° C. for 2to 24 hours.

(vii) Conversion of carboxyl group into an aryloxycarbonyl group: Thecarboxyl group of a compound having carboxyl group as the substituent R²among the compounds expressed by the formula (I) can be converted intoan aryloxycarbonyl group by reacting the compound with equivalent orexcess amount of a hydroxyl-containing aromatic compound such as phenolusing an aliphatic ether such as diethyl ether as a solvent in thepresence of a condensation agent such as dicyclohexylcarbodiimide. Thereaction is carried out usually at 0 to 50° C. for 1 to 48 hours,preferably at room temperature for 3 to 24 hours.

The carboxyl group of a compound having a carboxyl group as the R² groupcan be converted into carbamoyl group by conventional method such as theconversion of the carboxyl group to an acid halide with oxalyl chloride,etc., followed by the reaction of the product with ammonia water.Similarly, the acid halide can be converted toN-methyl-N-methoxycarbamoyl group by reacting withN-methyl-N-methoxyamine and the product can be converted further to analkylcarbonyl group by the reaction with various kinds of alkylmagnesiumreactants.

For a compound having amidino group as the substituent A among thecompounds of the present invention synthesized by the above methods,various carbonyl groups can be introduced to one of the nitrogen atomsconstituting the amidino group by the methods shown by (ix), (x) and(xi).

(ix) Aryloxycarbonylation reaction of amidino group: An aryloxycarbonylgroup can be introduced to one of the nitrogen atoms constituting theamidino group of a compound having amidino group as the substituent Aamong the compounds expressed by the formula (I) by stirring thecompound together with equivalent or excess amount of an arylchloroformate such as phenyl chloroformate in the presence of a basesuch as sodium hydroxide or potassium hydroxide in a mixture of waterand a halogenated hydrocarbon such as dichloromethane. The reaction iscarried out usually at −10 to +40° C. for 3 to 48 hours, preferablyusing equivalent or small excess amount of an aryl chloroformate at0-30° C. for 6 to 24 hours.

(x) Alkoxycarbonylation reaction of amidino group: An alkoxycarbonylgroup can be introduced to one of the nitrogen atoms constituting theamidino group of a compound having amidino group as the substituent Aamong the compounds expressed by the formula (I) by reacting thecompound with equivalent or excess amount of p-nitrophenylalkylcarbonate in an anhydrous solvent such as THF and DMF in thepresence of a metal hydride such as sodium hydride or a base such as atertiary amine at −10 to +30° C. for 3 to 48 hours. Preferably, thereaction is carried out by using equivalent to small excess amount of ap-nitrophenyl alkylcarbonate in the presence of a tertiary amine such astriethylamine or diusopropylethylamine at −10 to +40° C. for 6 to 24hours.

(xi) Arylcarbonylation reaction of amidino group: An arylcarbonyl groupcan be introduced to one of the nitrogen atoms constituting the amidinogroup of a compound having amidino group as the substituent A among thecompounds expressed by the formula (I) by reacting the compound withequivalent or excess amount of an aromatic carboxylic acid chloride suchas benzoyl chloride in a halogenated hydrocarbon such as methylenechloride, a solvent such as THF, DMF or pyridine or their mixture in thepresence of a base such as an amine at −10 to +30° C. for 1 to 48 hours.Preferably, the reaction is carried out by using equivalent to smallexcess amount of an aromatic carboxylic acid chloride in the presence ofan amine such as triethylamine or diusopropylethylamine at −10 to +40°C. for 2 to 24 hours.

The compound expressed by the formula (I) can be produced also by anarbitrary combination of known processes usually adoptable by personsskilled in the art such as etherification, amidination, hydrolysis,alkylimidoylation, amidation and esterification.

The alkoxymethylphenylbenzamidine derivative I produced by the abovemethod can be separated and purified by conventional methods such asextraction, precipitation, fractional chromatography, fractionalcrystallization and recrystallization. The pharmacologically permissiblesalt of the compound of the present invention can be produced by theconventional salt-forming reaction.

The medicinal composition of the present invention is characterized bythe property to reduce the contact of the compound of the presentinvention with components of bile or pancreatic juice secreted in theduodenum.

The reduction of the contact of the compound of the present inventionwith the components of bile or pancreatic juice means that the contactof the medicinal composition of the present invention with thecomponents of bile or pancreatic juice is reduced compared with acomposition usually taking a solution state in the stomach or aconventional oral administration drug quickly releasing the activecomponent in the stomach.

The composition of the present invention can avoid the suppression ofthe absorption of the compound by reducing the contact of the compoundof the present invention with the components of the bile or pancreaticjuice.

A release-site regulating preparation is a preferable embodiment of themedicinal composition of the present invention.

There is no particular restriction on the releasing mechanism of suchrelease-site regulating preparation provided that the medicinalcomposition can old the compound in the medicinal composition at leastdown to the duodenum to prevent the diffusion of the compound in thedigestive tract and release the compound when the medicinal compositionreaches the duodenum or the following small intestine or large intestineby its physiological condition or by a preparatorily integratedtime-dependent mechanism. Preferable examples of the medicinalcomposition are shown below.

Medicinal Composition (1)

A medicinal composition produced by coating the compound of the presentinvention with a pH-dependently soluble enteric polymer.

Medicinal Composition (2)

A medicinal composition containing the compound of the present inventionand a disintegrant, partly or totally covered its surface with awater-insoluble and water-permeable substance and having a mechanism tocause the collapse or opening after 0.5 to 5 hours when brought intocontact with water.

Medicinal Composition (3)

A medicinal composition produced by coating the compound of the presentinvention with a material decomposable by enteric bacteria indigenous tothe lower part of the small intestine to the large intestine.

These medicinal compositions (1) to (3) are explained in more detail.

The medicinal composition (1) is produced by coating a constituentcomponent containing the compound of the present invention with apH-dependently soluble enteric polymer, i.e. an enteric polymerresistant to dissolution below pH 4.5 and soluble at pH 4.5 or above.

The pH-dependent enteric polymer is, for example, anionic polymers suchas hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethyl ethylcellulose, celluloseacetate phthalate, cellulose acetate trimellitate, polyvinyl acetatephthalate and methacrylic acid copolymer.

The medicinal composition (2) is a composition containing the compoundof the present invention and a disintegrant and partly or totallycovered its surface with a layer composed of a water-insoluble andwater-permeable substance. The swelling of the disintegrant takes placeby the water permeated through the layer to cause the collapse or burstof the medicinal composition after the lapse of a prescribed period. Thelayer composed of the water-insoluble and water-permeable substance doesnot pass the compound.

The prescribed period means the time necessary to reach the medicinalcomposition to the duodenum having the opening of common bile duct todischarge the bile juice and pancreatic juice at high concentration orto pass the composition through the duodenum. The period is especiallydependent upon the time to discharge the composition from the stomach.The discharging time from the stomach is considerably dependent upon theingestion condition of food and the time of from several minutes to 24hours is reported by a literature (Biopharmaceutics of AdministeredDrugs; P. Macheras, C. Reppas and J. B. Dressman; p89-p123; EllisHorwood). When the state of the medicinal composition is between asuspension and a solid, the prescribed period is specified to 0.5 to 4.5hours taking consideration of the fact that the discharging period fromthe stomach is about 0.5 to 4.5 hours in the case of administering to anempty stomach or after a light meal.

Preferable examples of the water-insoluble and water-permeable substanceare ethylcellulose and cellulose acetate.

The disintegrant is preferably e.g. cellulose, cellulose lower alkylether, starch or its derivative.

The medicinal composition (3) is a composition produced by coating thecompound of the present invention with a material decomposable byenteric bacteria indigenous to the lower part of the small intestine tothe large intestine and releases the compound at the lower part of thedigestive tract by the decomposition of the coating material with theenteric bacteria.

The enteric bacteria mean bacteria indigenous mainly to the lower partof the small intestine to the large intestine.

The material to be decomposed by the enteric bacteria is preferably anazo-containing segmented polyurethane, chitosan, etc.

Each of the medicinal compositions (1), (2) and (3) may be incorporatedwith a base foamable by the generation of carbon dioxide gas when theenvironment reaches a prescribed physical condition or after the lapseof a prescribed period.

Preferable example of the base to generate carbon dioxide gas is acombination of sodium bicarbonate with citric acid, tartaric acid,fumaric acid or heir salts.

The medicinal composition of the present invention may be furtherincorporated as necessary with a pharmacologically permissibleexcipient.

The administration rate of the compound of the present invention dependsupon the kind of disease, administration method, symptom of the patient,age, sex, body weight, etc., and generally the rate is 1 to 1,000mg/day/head, preferably 10 to 300 mg/day/head by oral administration.

EXAMPLES

The present invention is described in more detail in the followingExamples, which do not restrict the scope of the invention.

Comparative Example 1

An aqueous solution (1.67 mg/mL) of3-(3-amidinophenyl)-5-[(1-acetimidoyl-4-piperidinyl)methylaminomethyl]benzoicacid (hereinafter referred to as compound (A)) was administered to fourfasted crab-eating monkeys of 5.5 to 7.0 kg body-weight at a rate of 5mg/kg (corresponding to 3 mL/kg of the solution) and about 2 mL each ofblood was collected at 7 points, i.e. immediately before theadministration of the compound (A) and 0.5, 1, 2, 4, 8 and 10 hoursafter the administration. The plasma was separated and the concentrationof the compound (A) was determined by LC/MS. The AUC (area under thecurve of concentration in plasma vs. time) and Cmax (maximumconcentration in plasma) were calculated as pharmacokinetic parametersby a moment analysis program. The results are collectively shown in theTable 1.

Example 1

The following experiments were performed by cross-over method using fourcrab-eating monkeys same as those used in the Comparative Example 1.

Powder of the compound (A) was encapsulated together with an excipientin a hard capsule made of M-type hydroxypropylmethyl cellulose acetatesuccinate (HPMCAS) (AQOAT; product of Shin-Etsu Chemical Co., Ltd.)having pH dependency and dissolving in the intestines. The capsules wereadministered to four fasted crab-eating monkeys of 5.5 to 7.0 kgbody-weight at a rate of 5 mg/kg and about 2 mL each of blood wascollected at 7 points, i.e. immediately before the administration of thecompound (A) and 0.5, 1, 2, 4, 8 and 10 hours after the administration.The plasma was separated and the concentration of the compound (A) wasdetermined by LC/MS. The AUC and Cmax were calculated by the method sameas the Comparative Example 1 and the results are collectively shown inthe Table 1.

TABLE 1 AUC (∞) Cmax Pharmacokinetic parameters mg.hr/L mg/L ComparativeExample 1 0.782 0.147 Example 1 1.179 0.112 Comparative Example 1:Aqueous solution of the compound (A) Example 1: Enteric capsulecontaining the compound (A)

Comparison between the Comparative Example 1 and the Example 1 revealedthat the value of Cmax was larger in the Comparative Example 1 whilethat of AUC was large in the Example 1 and the absorptivity of thecompound (A) was larger in the Example 1, suggesting that the absorptionof the composition (aqueous solution) of the Comparative Example wassuppressed by the contact with the components in the bile or pancreaticjuice and that the composition (enteric capsule) of the Example 1achieved decreased suppression of absorptivity by avoiding the contactwith the components in the bile or pancreatic juice.

Comparative Example 2

A tablet containing 3-(3-amidinophenyl)-5-[(1-acetimidoyl-4-piperidinyl)methylaminomethyl]benzoic acid(hereinafter referred to as compound (A)) was prepared as a comparativeexample by the following method. Namely, 12.50 grams of the compound(A), 114.25 grams of lactose (Dilactose R) and 2.6 grams ofcroscarmellose sodium (AcDisol, product of Asahi Chemical Industry) weremixed for 2 minutes with a high-speed agitation granulator (FDG-C5,product of Fukae Industry), added with 0.65 gram of magnesium stearateand mixed for 10 seconds. The mixed powder was tableted with asingle-shot tableting machine (KORSCH) to obtain a tablet (uncoatedtablet) having a principal drug content of 11.5 mg/tablet, an averageweight of 131.3 mg and a diameter of 7 mm.

The obtained uncoated tablet was administered to beagle dogs and thechange of the drug concentration in plasma was measured. A suspension ofloperamide hydrochloride was orally administered to four fasted beagledogs at a rate of 0.12 mg/mL/kg together with 15 mL of ion-exchangedwater and each dog was administered with two uncoated tablets eachcontaining 11.5 mg of the drug after 30 minutes and allowed to drink 20mL of ion-exchanged water. Blood was collected at 0.5, 1, 1, 2, 3, 4, 5,6, 8, 10 and 12 hours after the administration and the drugconcentration in plasma was determined. The pharmacokinetic parameterswere determined by moment analysis using the plasma concentration dataas a base. The results are shown in the Table 2. The Tmax (time to reachCmax) of the drug was 1 hour, the Cmax was 0.318 mg/L and the AUC(∞) was1.29 mg.hr/L.

Example 2

A mixture produced by mixing 28.8 grams of the compound (A), 263.7 gramsof lactose and 2.6 grams of croscarmellose sodium by a high-speedagitation granulator for 2 minutes was added with 0.65 gram of magnesiumstearate and mixed for 10 seconds. The mixed powder was tableted with asingle-shot tableting machine to obtain a tablet of 7 mm diameter.

The produced tablet was coated with a coating liquid composed of 554.1grams of purified water, 30.0 grams of hydroxypropylmethyl celluloseacetate succinate (AS-L-F type, product of Shin-Etsu Chemical Co.,Ltd.), 6.0 grams of triethyl citrate (citroflex 2, SC-60), 9.0 grams oftalc (product of Matsumura Sangyo Co.) and 0.9 gram of sodiumlaurylsulfate (product of Nikko Chemical Co.) by a coating machine(HCT-MINI, product of Freund Industrial Co.) to obtain an entericcoating tablet constituting the Example 2. The charged amount of theuncoated tablet was 250 grams and the heater temperature was set to 60°C. The content of the compound (A) in the obtained enteric coatingtablet was 11.5 mg/tablet.

The effect of the enteric coating was confirmed by the followingdissolution test. The tablets were put into 900 mL of the first fluid ofthe Japanese Pharmacopeia (pH 1.2), a buffer solution of pH 6.0 and thesecond fluid of the Japanese Pharmacopeia (pH 6.8) one for each fluidand the dissolution of the compound (A) was measured at 37° C. and 50rpm. The dissolution of the compound (A) was unobservable in the firstfluid of the Japanese Pharmacopeia even after 5 hours. In the buffersolution of pH 6.0, the dissolution ratio of the compound (A) was about20% after 15 minutes and about 100% after 30 minutes. In the secondfluid of the Japanese Pharmacopeia, the dissolution ratio of thecompound (A) was about 70% after 15 minutes and about 100% after 30minutes.

The experiment on the tablet of the Comparative Example 2 revealed thedissolution of about 100% of the compound (A) after 30 minutes in thefirst fluid of the Japanese Pharmacopeia (pH 1.2).

The enteric tablet obtained by the above Example 2 and quicklydissolving at pH 6 or above was administered to beagle dogs and thechange of the drug concentration in plasma was measured. A suspension ofloperamide hydrochloride was orally administered to four fasted beagledogs at a rate of 0.12 mg/mL/kg together with 15 mL of ion-exchangedwater and each dog was administered with two enteric tablets eachcontaining 11.5 mg of the drug after 30 minutes and allowed to drink 20mL of ion-exchanged water. Blood was collected at 0.5, 1, 2, 3, 4, 5, 6,8, 10 and 12 hours after the administration and the drug concentrationin plasma was determined. The pharmacokinetic parameters were determinedby moment analysis using the data as a base. The results are shown inthe Table 2. The Tmax of the drug was 1 hour, the Cmax was 0.341 mg/Land the AUC(∞) was 1.38 mg.hr/L. The Auc was increased and the retentiontime of the estimated effective blood concentration was prolongedcompared with the Comparative Example 2.

TABLE 2 AUC Cmax Tmax PK Parameter mg.hr/L mg/L hr Comparative Example 21.29 0.318 1.0 Example 2 1.38 0.341 1.0 Comparative Example 2: CompoundA tablet (uncoated tablet) Example 2: Compound A tablet (entericcoating, quick releasing)

Comparison between the Comparative Example 2 and the Example 2 revealedthat the absorbability of the composition of the Example 2 was higherbecause the values of AUC and Cmax were larger in the Example 2 comparedwith the Comparative Example 2. The fact suggests that the suppressionof the absorption of the compound A caused by the contact with thecomponents in the bile or pancreatic juice is avoided by theadministration of the compound in the form of an enteric coating tablet.

What is claimed is:
 1. A medicinal composition containing one or morecompounds selected from the group consisting of compounds represented byformula (I), salts of these compounds, solvates of these compounds andsolvates of these salts and a carrier, and wherein the composition iscapable of reducing contact of the said compounds with components inbile or pancreatic juice.

wherein: R¹ is hydrogen atom, fluorine atom, chlorine atom, bromineatom, hydroxyl group, amino group, nitro group, a C₁-C₈ alkyl group or aC₁-C₈ alkoxy group, L is direct bond or a C₁-C₄ alkylene group, R² isfluorine atom, chlorine atom, bromine atom, hydroxyl group, amino group,a C₁-C₈ alkoxy group, carboxyl group, a C₁-C₈ alkoxycarbonyl group, anaryloxycarbonyl group, an aralkoxycarbonyl group, carbamoyl group,wherein the nitrogen atom of the carbamoyl group may be substituted withmono- or di-C₁-C₈ alkyl group or may be the nitrogen atom of an aminoacid, a C₁-C₈ alkylcarbonyl group, a C₁-C₈ alkylsulfenyl group, a C₁-C₈alkylsulfinyl group, a C₁-C₈ alkylsulfonyl group, a mono- or di-C₁-C₈alkylamino group, a mono- or di-C₁-C₈ alkylaminosulfonyl group, sulfogroup, phosphono group, bis(hydroxycarbonyl)methyl group, abis(alkoxycarbonyl)methyl group or 5-tetrazolyl group, R³ is hydrogenatom, fluorine atom, chlorine atom, bromine atom, hydroxyl group, aminogroup, nitro group, a C₁-C₈ alkyl group, a C₁-C₈ alkoxy group, carboxylgroup or a C₁-C₈ alkoxycarbonyl group, X is a group of the formulas —O—,—S—, —SO—, —SO₂—, —NH—CO—NH—, —N(R⁴)—, —CO—N(R⁵)—, —N(R⁵)—CO—,—N(R⁵)—SO₂— or —SO₂—N(R⁵)—, wherein: R⁴ is hydrogen atom, a C₁-C₁₀ alkylgroup, a C₁-C₁₀ alkylcarbonyl group, a C₁-C₁₀ alkylsulfony) group, aC₃-C₈ cycloalkyl group or an aryl group, R⁵ is hydrogen atom, a C₁-C₁₀alkyl group, a C₃-C₈ cycloalkyl group or an aryl group, and wherein thealkyl groups represented by R⁴ and R⁵ may be substituted with an arylgroup, hydroxyl group, amino group, a halogen atom, a C₁-C₈ alkoxygroup, carboxyl group, a C₁-C₈ alkoxycarbonyl group, an aryloxycarbonylgroup, an aralkoxycarbonyl group, carbamoyl group or 5-tetrazolyl group,Y is a 6-membered ring group of the following formula I-1

 wherein: the methylene group of the ring system may be replaced with acarbonyl group and an unsaturated bond may be present in the ring, R⁶ ishydrogen atom, fluorine atom, chlorine atom, bromine atom, hydroxylgroup, amino group, nitro group, a C₁-C₈ alkyl group or a C₁-C₈ alkoxygroup, W is C—H, Z is hydrogen atom, a C₁-C₁₀ alkyl group which may besubstituted with hydroxyl group, excluding the case of a C₁ alkyl group,amino group, a C₁-C₈ alkoxy group, excluding the case of a C₁ alkylgroup, carboxyl group, a C₁-C₈ alkoxycarbonyl group, an aryloxycarbonylgroup or an aralkoxycarbonyl group, a C₁-C₈ alkylcarbonyl group, anarylcarbonyl group, an aralkylcarbonyl group, amidino group or a groupof the following formula I-3

 wherein: R⁷ is a C₁-C₈ alkyl group which may be substituted withhydroxyl group or a C₁-C₈ alkoxy group, an aralkyl group or an arylgroup, m is an integer of from 1 to 3, and n is an integer of from 0 to3.
 2. The medicinal composition according to claim 1 wherein thecompounds are not released until the composition reaches the duodenum,the remainder of the small intestine or the large intestine.
 3. Themedicinal composition according to claim 1 or 2 wherein the medicinalcomposition is coated with an enteric polymer resistant to dissolutionbelow pH 4.5 and soluble at pH 4.5 or above.
 4. The medicinalcomposition according to claim 3 wherein said enteric polymer is one ormore kinds selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl cellulose phthalate,carboxymethyl ethylcellulose, cellulose acetate phthalate, celluloseacetate trimellitate, polyvinyl acetate phthalate and methacrylic acidcopolymer.
 5. The medicinal composition according to claim 1 or 2wherein the medicinal composition additionally contains a disintegrant,and is coated totally or partly with a water-insoluble andwater-permeable substance, and wherein the coated composition has amechanism to destroy or open the coated composition upon contact withwater for 0.5 to 4.5 hours.
 6. The medicinal composition according toclaim 1 or 2 wherein said compound is coated with a materialdecomposable by enteric bacteria indigenous to the lower part of thesmall intestine and to the large intestine.